title: Hypothesis testing: is clozapine's superior efficacy dependent on moderate D2 receptor occupancy?
abstract: BACKGROUND
  How clozapine exerts superior antipsychotic efficacy in treatment-resistant schizophrenia is not known. Moderate (rather than "full") occupancy of D2 postsynaptic receptors may be crucial, perhaps by achieving a more effective D1/D2 or serotonin-2a/D2 ratio. The objective of this study was to test the moderate occupancy hypothesis of clozapine's superior efficacy.
  
  
  METHODS
  Data from the New York effectiveness of clozapine study were used to compare 6-week clozapine treatment results in patients discontinuing oral neuroleptic medication with similar patients discontinuing long-acting depot neuroleptic. The latter group is assured "full" D2 occupancy during the 6-week clozapine treatment.
  
  
  RESULTS
  If moderate occupancy is crucial for superior efficacy, the oral discontinuation group should manifest more improvement. Both groups showed the 6-week improvement expected with clozapine therapeutics [31% and 29% reduction in Brief Psychiatric Rating Scale (BPRS) scores in the depot and oral groups, respectively]. An analysis of covariance (for baseline BPRS) revealed no difference in change scores (df = 1,100; F = 0.17; p = ns).
  
  
  CONCLUSIONS
  The reduced D2 occupancy hypothesis is rejected.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Carpenter
authors.forename: J M
authors.initials: JM
authors.lastname: Zito
authors.forename: J
authors.initials: J
authors.lastname: Vitrai
authors.forename: J
authors.initials: J
authors.lastname: Volavka
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D006801:Humans; D011569:Psychiatric Status Rating Scales; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003024:Clozapine